Encephalitis – a success story

Akila Narasimhan1, PV Nimisha1, Suresh Chelliah1,*, Duraisamy Senguttuvan1,Sivagurunathan Panchanathan2, Bichalu Mythili2

1Department of Pediatrics, Kauvery Hospital, Trichy, Tamilnadu, India

2Department of Pediatrics, KAPV Medical College, Trichy, Tamilnadu, India

*Correspondence: chelliah.suresh@yahoo.co.in

Abstract

Background Autoimmune encephalitis is being increasingly and frequently diagnosed in children with acute and sub-acute encephalopathy because of advances in imaging and molecular diagnostic tests.

Case presentation A 6-years-old girl, with no previous neurological abnormalities, presented with history of fever for six days, vomiting, generalised tonic-clonic seizures (GTCS), two episodes in three days and unconsciousness since the onset of seizure. Examination was unremarkable but for altered sensorium. Auto immune encephalitis was suspected and diagnosed on the basis of positive anti N-methyl-D-aspartate receptor (NMDAr) antibodies. She required intensive care, methyl prednisolone, intravenous immunoglobulin (IVIg), rituximab and cyclophosphamide. After intensive physiotherapy following recovery child is clinically well now.

Conclusion Autoimmune encephalitis is not so uncommon. Prompt diagnosis and intensive therapy yields satisfactory results.

Keywords Autoimmune encephalitis, NMDA receptor antibodies, rituximab, cyclophosphamide

Background

Autoimmune encephalitis (AIE) is being increasingly recognized as a significant as well as frequent cause of encephalopathy in the paediatric age group. Despite a plethora of antibodies being described against the central nervous system, a significant proportion of childhood autoimmune encephalitis do not exhibit detectable known antibodies, making it a diagnostic challenge [1]

Case Presentation

A 6-years-old girl, with no previous neurological abnormalities, presented with low grade intermittent fever for six days, vomiting, three to four episodes per day for six days, seizure episodes-GTCS, lasting less than 10 min – two episodes in three days and unconsciousness since the onset of seizure.

On admission, she had altered sensorium with Glasgow coma scale of 7/15, with normal respiratory effort, 24 per min and normal pupils. Pulse rate was 140 per min. Capillary blood sugar 101 mg, temperature 98°F. She was thinly built with normal height and had no neurocutaneous markers. Examination revealed hypotonia, with exaggerated deep tendon reflexes (DTR) and bilateral extensor plantars. There was no sign of meningeal irritation. Acute meningo-encephalitis with probable viral aetiology was considered. Differential thought of was autoimmune encephalitis, as the onset of seizure and altered sensorium was on the fourth day of fever. She required oxygen, antibiotics, antiviral, multiple anticonvulsants and neuroprotective measures.

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Investigations

There was leucocytosis, normal CRP, liver enzymes, electrolytes and renal function test. MRI brain showed T2 flair hyper intensity in basal ganglia, caudate nucleus. Cerebrospinal fluid (CSF) analysis showed WBC 13, normal protein and sugar.

Course She was intubated on the second day and started on midazolam infusion as she had recurrent seizure episodes.

Auto immune encephalitis was considered and after sending CSF for further studies, she was started on pulse IV methylprednisolone with other anticonvulsants. She developed extrapyramidal symptoms for which oral pacitane and haloperidol were added. Both blood and CSF cultures were sterile, CSF for Japanese encephalitis, CBNaat and viral panel were negative.

CSF antiNMDA receptor antibody was positive. She was treated with IVIg 0.5 g per kg for three days, and pulse steroids were given for five days. EEG showed bilateral intermittent slow waves and predominant theta waves. MRI screening abdomen done to rule out ovarian tumours was normal. Her sensorium showed some improvement, but abnormal movements persisted. Tracheostomy was done on Day 8 of admission. She developed fever spikes and tachypnoea. Chest x-ray showed bilateral pneumothorax. Intercostal drainage tube was inserted.

On Day 10 of admission, she was shifted to Trichy Medical College Hospital as requested by parents after consulting with paediatricians who readily accepted to take over. Ventilation and physiotherapy were continued with other supportive care. Tracheal culture grew Acinetobacter, and urine culture showed Candida sp. Appropriate antibiotics were continued. MRI brain repeated after one week showed features of encephalitis. She received another pulse of methylprednisolone, six cycles of IV cyclophosphamide and weekly dose of IV rituximab 375mg per m2 under cardiac monitoring.

On Day 38, tracheostomy removed and physiotherapy was continued. At discharge she was still not recognising her mother, and had emotional outbursts like screaming episodes and sleep disturbances. Involuntary movements had decreased significantly. Parents were advised to follow up and to continue occupational therapy. She was discharged after three months in the hospital.

At review in our hospital four weeks later, she was recognising her parents, walking with slightly unsteady gait, and talking normally.

Discussion

Advances in imaging, antibody detection and genomic studies has revolutionized diagnostics in many fields, more so in the hitherto unreachable neurological sciences. AIE is one such diagnosis that is frequently made now, when commoner causes of encephalitis and encephalopathy are ruled out. The most common antibody associated with AIE in children is anti-NMDA receptor (NMDAr) antibody [1].

Anti-NMDAr encephalitis accounts for 4% of all encephalitis and is the most common cause of seropositive AIE in children [2]. Almost 40% of all reported cases are below 18 years of age. Anti-NMDAr encephalitis may also contribute to recurrence of encephalitis following herpes simplex virus encephalitis in both children and adult. Other non-herpes viruses may also act as triggers for anti-NMDAr encephalitis.

Clinical features include a prodrome in 50% of cases lasting weeks to months comprising fever, malaise, headache, gastrointestinal or respiratory complaints followed by neurological (abnormal behaviour, cognitive deterioration, short-term memory loss, seizures, movement disorders, central hypoventilation syndrome), psychiatric (delusions, hallucinations, catatonia) and autonomic dysfunction [3]. Seizures, seen in up to 80% of patients, may be focal or generalized, including status epilepticus, and may occur in any stage of the disease. Movement disorders include orofacial dyskinesia, chorea-athetosis, ballismus, rigidity, opisthotonus and tremors. Advanced disease is characterized by stupor, coma, and periods of agitation alternating with catatonia as well as autonomic dysfunction.

Types known Classic form and the psychiatric form (associated with good outcomes) and the catatonia-predominant form (associated with poor outcome). Corticosteroids form the cornerstone of treatment. They have good penetration across the blood brain barrier and have a broad spectrum of anti-inflammatory activity. IVIg and plasma exchange are the other alternatives. If the patient does not respond to first line therapy, or if the disease is severe or relapsing, treatment with a second-line agents like cyclophosphamide and rituximab improves prognosis [4].

Most patients with anti-NMDAr encephalitis respond to immune therapy. A study with a median follow up of 24 months showed that 94% patients responded within four weeks to first line immunotherapy or tumour removal [5]. Of the patients who failed first line therapy, 57% underwent second line therapy and had better outcomes. At 24 months follow up, 81% patients had a good outcome, with mortality in 6%. Outcomes continued to improve up to 18 months following treatment. Predictors of good outcome included early treatment and lack of intensive care unit admission [5]

 

Conclusion

Autoimmune encephalitis is not so uncommon in clinical practice and should be considered whenever clinical features and investigations do not point to more common causes of encephalitis namely infections and toxins. Prompt diagnosis and intensive therapy yields satisfactory results.

Acknowledgements

We would like to thank our colleagues in the Department of Paediatric, Kauvery Hospital and KAPV Medical College Hospital, Trichy for their contribution towards the treatment of this child and many like her

Author contributions

All the authors were involved in the management of the child. PV Nimisha and Suresh Chelliah drafted the manuscript.

Competing interests

The authors have no competing interest to declare.

References

  1. Hacohen Y, Wright S, Waters P, et al. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens. J Neurol Neurosurg Psychiatry. 2013;84(7):748-755.
  2. Barbagallo M, Vitaliti G, Pavone P, et al. Pediatric autoimmune encephalitis. J Pediatr Neurosci. 2017;12(2):130.
  3. Matthew SK, Josep D, et al. Anti-NMDA receptor encephalitis in psychiatry. Curr Psychiatry Rev. 2011;7(3):189-193.
  4. Nosadini M, Mohammad SS, Ramanathan S, et al. Immune therapy in autoimmune encephalitis: a systematic review. Expert Rev Neurother. 2015;15(12):1391-1419
  5. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157-165.

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